Common inherited DNA variants are expected to play an important role in colorectal cancer (CRC). However, the main effects for these variants are likely to be weak because as much as 75-80% of CRC cases are explainable by known or suspected lifestyle risk factors. Most importantly, recent evidence suggests that common genetic factors for CRC act by amplifying these environmental effects. It is now practical to comprehensively study association with inherited DNA variation genome-wide. We propose to build on existing collaborations to undertake such a study using a multiethnic cohort representing the diversity of the U.S. population and a Japanese cohort. We have established a large biorepository linked to detailed, pre-diagnostic lifestyle exposure information and clinical data for five racial-ethnic groups in the Multiethnic Cohort study (MEC), as well as for Japanese in Japan in the Japan Public Health Center cohort study (JPHC). We will perform a two-stage, well powered, population-based, genome-wide association study of CRC in the MEC and JPHC, concentrating on both main effects and gene-environment interactions. In Stage 1, we will test ~1 million single nucleotide polymorphisms (SNPs) for association with CRC in 1,000 cases and 1,000 controls of Japanese ancestry from the MEC and evaluate both the main effects of each SNP (overall and for colon and rectal cancers) and their interactions with a well-defined set of lifestyle variables (folate, red meat, alcohol and calcium intakes, and BMI and pack-years). About 16,000 of the most strongly associated variants (singly, by anatomical subsite, or interacting with these lifestyle risk factors) with risk will be further evaluated in Stage 2, using additional subjects, consisting of 3,000 CRC cases and 3,000 controls from the MEC (African Americans, Japanese Americans, Latinos, Native Hawaiians and Whites) and JPHC (Japanese). Significance and heterogeneity of effects will be assessed using a combined analysis of Stages 1 and 2. Data from this study will quickly be made available to the research community. The elucidation of modifying genes for CRC will identify new mechanistic pathways and generate a better biological understanding on which to base individual risk assessment and new therapeutic approaches. PUBLIC HEALTH RELEVANCE: This multiethnic study will interrogate the entire genome for association with inherited genetic variants that may increase risk of colorectal cancer, either independently or by amplifying the effects of specific lifestyle risk factors. The study will generate a better biological understanding of the disease on which to base new prevention and therapeutic approaches.